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bioRxiv · 10.1101/2023.01.20.524912

PPAR-γ is a promising therapeutic target for memory deficits induced by early alcohol exposure.

Garcia-Baos, A.·Pastor, A.·Gallego-Landin, I.·de la Torre, R.·Sanz, F.·Valverde, O.
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Abstract

BackgroundPatients diagnosed with fetal alcohol spectrum disorder (FASD) show persistent cognitive disabilities, including memory deficits. However, the neurobiological substrates of these deficits remain unclear. Here, we studied the participation of the expanded endocannabinoid system (ECS), which is known to be affected by alcohol in other life periods, and it is involved in memory impairments of neurodevelopmental disorders. MethodsC57BL/6 female mice were exposed to a time-limited access to either water or alcohol to model prenatal and lactation alcohol exposure (PLAE). The expanded ECS was analyzed in the prefrontal cortex and the hippocampus of the offspring at post-partum day (PD) 25 and 70. Then, memory performance was tested after the repeated administration (from PD25 to PD34) of: i) URB597, to increase N-acylethanolamines (NAEs), and GW9662, a peroxisome proliferator-activated receptor gamma (PPAR-{gamma}) antagonist; ii) pioglitazone, a PPAR-{gamma} agonist. Finally, we used a viral approach to upregulate astrocytic PPAR-{gamma} in the hippocampus to restore memory deficits. ResultsWe report that PLAE causes a hippocampal reduction of NAEs and PPAR-{gamma} at PD25. Moreover, URB597 suppresses PLAE-induced memory deficits through PPAR-{gamma}, since its effects are prevented by GW9662. Direct PPAR-{gamma} activation, using pioglitazone, also ameliorates memory impairments. Lastly, we demonstrate that the upregulation of PPAR-{gamma} in hippocampal astrocytes is sufficient to rescue PLAE-induced memory deficits. ConclusionOur data reveal a bidirectional link between memory deficits and expanded ECS alterations in the context of early alcohol exposure. Furthermore, we proved that PPAR-{gamma} in hippocampal astrocytes represents a specific therapeutic target for memory deficits in FASD.

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Garcia-Baos, A., Pastor, A., Gallego-Landin, I., de la Torre, R., Sanz, F., Valverde, O.. 2023-01-21. PPAR-γ is a promising therapeutic target for memory deficits induced by early alcohol exposure.. https://doi.org/10.1101/2023.01.20.524912

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